SUMMARY Exposure to toxicants has been linked to the development or exacerbation of chronic disease. While the health of effects of ubiquitous environmental substances such as tobacco smoke and particulate matter are more well-studied, less is known about how volatile organic chemicals (VOC)?a class of toxicants associated with higher prevalence of type 2 diabetes (T2D) and stroke?promote the development of cardiometabolic disease (CMD). Understanding how VOC affect CMD is important because obesity and T2D are rapidly growing global health crises. Accordingly, the overarching goals of this Superfund project are to determine the mechanisms by which VOCs negatively impact cardiovascular health and metabolism, identify biomarkers for VOC exposure and vascular injury, and test therapeutic strategies to minimize VOC-induced CMD. Our preliminary data suggest that VOC such as acrolein promote endoplasmic reticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells, resulting in insulin resistance. In addition, we find that individuals exposed to VOC such a vinyl chloride develop symptoms of CMD that could be instigated at the molecular level by VOC-induced ER stress. Specifically, we hypothesize that aldehyde metabolites of VOC, which are generally more toxic than their parent compound, diminish insulin sensitivity in vascular tissues by inducing ER stress, which triggers metabolic changes that accelerate ectopic lipid deposition and promote cardiometabolic dysfunction. To test this hypothesis we will: (1) examine the effects of VOC exposure on endothelial function and insulin resistance; (2) delineate the contribution of endothelial UPR to the cardiometabolic toxicity of VOC; and (3) elucidate the role of VOC-derived aldehydes in exacerbating CMD. The design of these studies includes molecular and pharmacological interventions designed to detoxify or quench the reactive intermediates evoked by VOC exposure as well as studies that could lead to the identification of novel, sensitive and robust biomarkers of both VOC exposure and vascular injury. These studies were designed to synergize with and provide biological plausibility for the associations identified in Project 1. Successful completion of this project will lead to identification of the underlying cellular and molecular mechanisms by which VOC affect insulin sensitivity and cardiometabolic function and provide insights into how VOC toxicity could be prevented or therapeutically minimized by targeting aldehydes or protein-folding pathways.